WO2017082760A1 - Dichloroacétate de {3-[4-(7н-pyrrolo[2,3-d] pyrimidine-4-yle)-pyrazole-1-yle]-1-éthylsulfonyle-azétidine-3-yle}-acétonitrile en qualité d'inhibiteur de janus-kinases - Google Patents

Dichloroacétate de {3-[4-(7н-pyrrolo[2,3-d] pyrimidine-4-yle)-pyrazole-1-yle]-1-éthylsulfonyle-azétidine-3-yle}-acétonitrile en qualité d'inhibiteur de janus-kinases Download PDF

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Publication number
WO2017082760A1
WO2017082760A1 PCT/RU2015/000879 RU2015000879W WO2017082760A1 WO 2017082760 A1 WO2017082760 A1 WO 2017082760A1 RU 2015000879 W RU2015000879 W RU 2015000879W WO 2017082760 A1 WO2017082760 A1 WO 2017082760A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
pyrrolo
pyrimidin
azetidin
Prior art date
Application number
PCT/RU2015/000879
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English (en)
Russian (ru)
Inventor
Алексей Евгеньевич РЕПИК
Александр Васильевич ИВАЩЕНКО
Василий Геннадьевич ИГНАТЬЕВ
Михаил Айратович ШАФЕЕВ
Original Assignee
Акционерное Общество "Р-Фарм" (Ao "Р-Фарм")
Алексей Евгеньевич РЕПИК
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Application filed by Акционерное Общество "Р-Фарм" (Ao "Р-Фарм"), Алексей Евгеньевич РЕПИК filed Critical Акционерное Общество "Р-Фарм" (Ao "Р-Фарм")
Publication of WO2017082760A1 publication Critical patent/WO2017082760A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • the present invention relates to dichloroacetate of substituted ⁇ 3 - [(7H-pyrrolo [2,3-] pyrimidin-4-yl) -azolyl] azetidine, as well as its compositions, methods of use and preparation.
  • This compound and its compositions are inhibitors of Janus kinases (JAK) and can be used in the treatment of JAK associated diseases, including, for example, inflammatory and autoimmune disorders, as well as cancer.
  • JAK Janus kinases
  • Oncogenic protein kinases are one of the largest and most attractive groups of protein targets for drug development. Janus kinases play an important role in the cytokine-dependent regulation of proliferation and function of cells involved in the immune response.
  • JAK1, JAK2, JAK3 also known as white blood cell Janus kinase; JAKL; L-JAK
  • TYK2 also known as protein tyrosine kinase 2
  • Blocking signal transmission at the level of JAK kinases is promising for the development of methods for treating inflammatory diseases, autoimmune diseases, myeloproliferative and human cancers.
  • An object of the present invention is to provide a novel JAK inhibitor for the treatment of rheumatoid arthritis, cancer and other diseases.
  • Baricitinib was chosen, which is the most advanced JAK inhibitor and is currently undergoing phase III clinical trials [NCT02340104, NCT0226391 1, NCT01710358; J.D. Clark, M.E. Flanagan, J.-B. Telliez. Discovery and Development of Janus Kinase (JAK) Inhibitors for Inflammatory Diseases. J. Med. Chem. 2014, 57, 5023-5038].
  • the ⁇ 3- [4- (7H-pyrrolo [2,3-c1] pyrimidin-4-yl) pyrazol-1-yl] -1-ethylsulfonyl-azetidin-3-yl ⁇ -acetonitrile dichloroacetate (1) of the present invention inhibits JAK activity.
  • the term "inhibit” means the ability to reduce the activity of one or more members of the JA family. Accordingly, a compound of formula (1) can be used in methods of inhibiting JAK activity.
  • An object of the present invention is a method of treating diseases or disorders in patients associated with JAK by administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • Example 1 Dichloroacetate ⁇ 3- [4- (7H-pyrrolo [2,3- (1] pyrimidin-4-yl) pyrazol-1-yl] -1-ethylsulfonyl-azetidin-3-yl ⁇ -acetonitrile (1 ) To a solution of 133 mg (0.36 mmol) ⁇ 3- [4- (7H-pyrrolo [2,3- ⁇ 1] pyrimidin-4-yl) -pyrazol-1-yl] -1-ethylsulfonyl-azetidin-3- silt ⁇ - acetonitrile in 10 ml of tetrahydrofuran was added 46.2 mg (0.36 mmol) of dichloroacetic acid.
  • Solubility ( ⁇ , ⁇ filtrate- ⁇ ⁇ blank) / Slope x 1.67 x Filtrate dilution
  • Example 3 Compounds were tested in accordance with Life Technologi's standard ⁇ -Lyte screening protocol). Test compounds are tested in 1% DMSO (final) in the well. 100 nl JOx of test compounds in 100% DMSO add 2.4 ⁇ l kinase buffer (50 mM HEPES, pH 6.5, 0.01% BRIJ-35, 10 mM MgC12, 1 mM EGTA, 0.02% NaN3) under conditions low volume NBS, black 384-well plate (Corning Cat. # 4514).
  • 2.4 ⁇ l kinase buffer 50 mM HEPES, pH 6.5, 0.01% BRIJ-35, 10 mM MgC12, 1 mM EGTA, 0.02% NaN3
  • the emission factor will remain low if the Lada peptide is not phosphorylated (i.e., not kinase inhibition) and will be high if the Lada peptide is non-phosphorylated (i.e., kinase inhibition).
  • the invention can be used in medicine and veterinary medicine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Le but de la présente invention est de produire un nouveau inhibiteur de JAK pour le traitement de l'arthrite rhumatoïde, du cancer et d'autres maladies. Cet objectif est atteint grâce à un dichloroacétate de {3-[4-(7Н-pyrrolo[2,3-D] pyrimidine-4-yle)-pyrazole-1-yle]-1-éthylsulfonyle-azétidine-3-yle}-acétonitrile correspondant à la formule 1, ou un soluté de celui-ci.
PCT/RU2015/000879 2015-11-13 2015-12-14 Dichloroacétate de {3-[4-(7н-pyrrolo[2,3-d] pyrimidine-4-yle)-pyrazole-1-yle]-1-éthylsulfonyle-azétidine-3-yle}-acétonitrile en qualité d'inhibiteur de janus-kinases WO2017082760A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
RU2015148809 2015-11-13
RU2015148809/04A RU2603959C1 (ru) 2015-11-13 2015-11-13 ДИХЛОРАЦЕТАТ {3-[4-(7H-ПИРРОЛО[2,3-d]ПИРИМИДИН-4-ИЛ)-ПИРАЗОЛ-1-ИЛ]-1-ЭТИЛСУЛЬФОНИЛ-АЗЕТИДИН-3-ИЛ}-АЦЕТОНИТРИЛА В КАЧЕСТВЕ ИНГИБИТОРА ЯНУС КИНАЗ

Publications (1)

Publication Number Publication Date
WO2017082760A1 true WO2017082760A1 (fr) 2017-05-18

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PCT/RU2015/000879 WO2017082760A1 (fr) 2015-11-13 2015-12-14 Dichloroacétate de {3-[4-(7н-pyrrolo[2,3-d] pyrimidine-4-yle)-pyrazole-1-yle]-1-éthylsulfonyle-azétidine-3-yle}-acétonitrile en qualité d'inhibiteur de janus-kinases

Country Status (2)

Country Link
RU (1) RU2603959C1 (fr)
WO (1) WO2017082760A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10766900B2 (en) 2017-12-29 2020-09-08 Formosa Laboratories, Inc. Baricitinib intermediate, method for forming Baricitinib intermediate, and method for preparing Baricitinib or pharmaceutically acceptable salt thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009114512A1 (fr) * 2008-03-11 2009-09-17 Incyte Corporation Dérivés d'azétidine et de cyclobutane en tant qu'inhibiteurs de janus kinase (jak)
EA201590321A1 (ru) * 2012-08-17 2015-06-30 Консерт Фармасьютикалс Инк. Дейтерированный барицитиниб
WO2015166434A1 (fr) * 2014-05-01 2015-11-05 Sun Pharmaceutical Industries Limited Forme cristalline de baricitinib

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160045498A1 (en) * 2013-04-04 2016-02-18 The Walter And Eliza Hall Institute Of Medical Research Methods of treating diseases characterized by excessive wnt signalling

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009114512A1 (fr) * 2008-03-11 2009-09-17 Incyte Corporation Dérivés d'azétidine et de cyclobutane en tant qu'inhibiteurs de janus kinase (jak)
EA201590321A1 (ru) * 2012-08-17 2015-06-30 Консерт Фармасьютикалс Инк. Дейтерированный барицитиниб
WO2015166434A1 (fr) * 2014-05-01 2015-11-05 Sun Pharmaceutical Industries Limited Forme cristalline de baricitinib

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10766900B2 (en) 2017-12-29 2020-09-08 Formosa Laboratories, Inc. Baricitinib intermediate, method for forming Baricitinib intermediate, and method for preparing Baricitinib or pharmaceutically acceptable salt thereof

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